Home LiteratureArticle Details
PMID: 3785192 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

A foreign dihydrofolate reductase gene in transgenic mice acts as a dominant mutation.

Molecular and cellular biology ·Vol. 6 ·No. 6 ·1986-06-00 ·Pages 2158-67

Gordon JW

Abstract

We have produced 17 lines of transgenic mice by microinjecting a full-length cDNA clone of an altered dihydrofolate reductase (dhfr) gene. The protein specified by this gene carries a point mutation which triples its Km for dihydrofolate and reduces substrate turnover 20-fold relative to the wild-type enzyme. Transgenic mice from different pedigrees, several of which carry a single copy of this gene in different integration sites, manifest an array of similar developmental abnormalities including growth stunting, reduced fertility, pigmentation changes, and skeletal defects. These defects appear in animals heterozygous for the foreign gene. RNA analyses demonstrate significant expression of the cDNA in newborn mice and adult tissues. These findings show that the additional dhfr gene exerts its mutational effects in a dominant fashion, and therefore the data indicate that transgenic mice can serve as models for elucidating mechanisms of dominant mutagenesis.

MeSH Terms
Animals Cleavage Stage, Ovum Female Fetal Death Gene Expression Regulation Genes, Dominant Infertility, Female Mice Mice, Mutant Strains/embryology,genetics,growth & development Phenotype Pregnancy RNA, Messenger/genetics Tetrahydrofolate Dehydrogenase/genetics Transfection
Chemicals
RNA, Messenger Tetrahydrofolate Dehydrogenase
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Gordon J W
References (49)
49 references, click to expand
  1. Correcting an immune-response deficiency by creating E alpha gene transgenic mice.
    Nature. 1985 Jul 4-10;316(6023):38-42 PMID: 3925351
  2. Metallothionein-human GH fusion genes stimulate growth of mice.
    Science. 1983 Nov 18;222(4625):809-14 PMID: 6356363
  3. Developmental regulation of alpha-fetoprotein genes in transgenic mice.
    Mol Cell Biol. 1985 Jul;5(7):1639-48 PMID: 2410773
  4. Association of the lethal yellow (Ay) coat color mutation with an ecotropic murine leukemia virus genome.
    Proc Natl Acad Sci U S A. 1983 Jan;80(1):247-9 PMID: 6296870
  5. SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice.
    Nature. 1985 Aug 1-7;316(6027):457-60 PMID: 2991771
  6. Insertion of retrovirus into the first intron of alpha 1(I) collagen gene to embryonic lethal mutation in mice.
    Proc Natl Acad Sci U S A. 1984 Mar;81(5):1504-8 PMID: 6324198
  7. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs.
    Cell. 1981 Nov;27(1 Pt 2):223-31 PMID: 6276022
  8. Characterization and localization of proopiomelanocortin messenger RNA in the adult rat testis.
    Science. 1984 Aug 10;225(4662):632-4 PMID: 6740329
  9. Expression of a microinjected immunoglobulin gene in the spleen of transgenic mice.
    Nature. 1983 Nov 24-30;306(5941):332-6 PMID: 6417544
  10. Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring.
    Cell. 1982 Jun;29(2):701-10 PMID: 7116454
  11. Analysis of a transgenic mouse containing simian virus 40 and v-myc sequences.
    Mol Cell Biol. 1985 Apr;5(4):642-8 PMID: 2985963
  12. Dilute (d) coat colour mutation of DBA/2J mice is associated with the site of integration of an ecotropic MuLV genome.
    Nature. 1981 Oct 1;293(5831):370-4 PMID: 6268990
  13. Specific expression of a foreign beta-globin gene in erythroid cells of transgenic mice.
    Nature. 1985 Mar 28-Apr 3;314(6009):377-80 PMID: 3982505
  14. Embryonic lethal mutation in mice induced by retrovirus insertion into the alpha 1(I) collagen gene.
    Nature. 1983 Jul 28-Aug 3;304(5924):315-20 PMID: 6308457
  15. Human beta-globin gene sequences injected into mouse eggs, retained in adults, and transmitted to progeny.
    Science. 1982 Sep 10;217(4564):1046-8 PMID: 6287575
  16. Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice.
    Nature. 1984 Dec 6-12;312(5994):517-20 PMID: 6438533
  17. Expression of human HPRT in the central nervous system of transgenic mice.
    Nature. 1985 Sep 19-25;317(6034):250-2 PMID: 2995815
  18. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody.
    Cell. 1984 Oct;38(3):647-58 PMID: 6091894
  19. Erythroid-specific expression of human beta-globin genes in transgenic mice.
    EMBO J. 1985 Jul;4(7):1715-23 PMID: 2992937
  20. Expression of the chicken transferrin gene in transgenic mice.
    Cell. 1983 Sep;34(2):335-41 PMID: 6311428
  21. Genetic mosaics of the rudimentary locus of Drosophila melanogaster: a genetical investigation into the physiology of pyrimidine synthesis.
    Dev Biol. 1977 Jul 1;58(1):134-47 PMID: 406154
  22. Detection of specific sequences among DNA fragments separated by gel electrophoresis.
    J Mol Biol. 1975 Nov 5;98(3):503-17 PMID: 1195397
  23. Properties of an altered dihydrofolate reductase encoded by amplified genes in cultured mouse fibroblasts.
    J Biol Chem. 1981 Sep 25;256(18):9501-10 PMID: 7287696
  24. Ribonucleic acid isolated by cesium chloride centrifugation.
    Biochemistry. 1974 Jun 4;13(12):2633-7 PMID: 4831907
  25. Effect of azaserine and other growth-inhibiting agents on fetal development of the rat.
    Cancer. 1956 Sep-Oct;9(5):955-62 PMID: 13364881
  26. DNA-mediated genetic transformation of mouse embryos and bone marrow--a review.
    Gene. 1985;33(2):121-36 PMID: 3888781
  27. Structure of amplified normal and variant dihydrofolate reductase genes in mouse sarcoma S180 cells.
    J Biol Chem. 1982 Jul 10;257(13):7887-97 PMID: 6282858
  28. An inherited limb deformity created by insertional mutagenesis in a transgenic mouse.
    Nature. 1985 Nov 7-13;318(6041):36-40 PMID: 2997621
  29. Prenatal lethalities in mice homozygous for human growth hormone gene sequences integrated in the germ line.
    Cell. 1983 Dec;35(3 Pt 2):647-55 PMID: 6580963
  30. The rudimentary locus of Drosophila melanogaster.
    J Mol Biol. 1984 May 5;175(1):1-17 PMID: 6144799
  31. Effect of certain 2,4-diaminopyrimidine antagonists of folic acid on pregnancy and rat fetus.
    Proc Soc Exp Biol Med. 1954 Dec;87(3):571-7 PMID: 13237310
  32. Transmission distortion and mosaicism in an unusual transgenic mouse pedigree.
    Cell. 1984 Apr;36(4):869-77 PMID: 6323025
  33. Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection.
    Methods Enzymol. 1983;101:411-33 PMID: 6577257
  34. Introduction of a rabbit beta-globin gene into the mouse germ line.
    Nature. 1981 Nov 5;294(5836):92-4 PMID: 6945481
  35. Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors.
    Cell. 1984 Jun;37(2):367-79 PMID: 6327063
  36. A foreign beta-globin gene in transgenic mice: integration at abnormal chromosomal positions and expression in inappropriate tissues.
    Cell. 1983 Sep;34(2):343-58 PMID: 6616614
  37. Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization by using dextran sulfate.
    Proc Natl Acad Sci U S A. 1979 Aug;76(8):3683-7 PMID: 291033
  38. Tissue-specific expression of the rat pancreatic elastase I gene in transgenic mice.
    Cell. 1984 Oct;38(3):639-46 PMID: 6567483
  39. Rapid DNA isolations for enzymatic and hybridization analysis.
    Methods Enzymol. 1980;65(1):404-11 PMID: 6246361
  40. Integration and stable germ line transmission of genes injected into mouse pronuclei.
    Science. 1981 Dec 11;214(4526):1244-6 PMID: 6272397
  41. Peripheral neuropathies, hepatocellular carcinomas and islet cell adenomas in transgenic mice.
    Nature. 1985 Aug 1-7;316(6027):461-3 PMID: 2991772
  42. Genetic transformation of mouse embryos by microinjection of purified DNA.
    Proc Natl Acad Sci U S A. 1980 Dec;77(12):7380-4 PMID: 6261253
  43. Germline integration of moloney murine leukemia virus at the Mov13 locus leads to recessive lethal mutation and early embryonic death.
    Cell. 1983 Jan;32(1):209-16 PMID: 6825169
  44. A general method for isolation of high molecular weight DNA from eukaryotes.
    Nucleic Acids Res. 1976 Sep;3(9):2303-8 PMID: 987581
  45. Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus.
    Proc Natl Acad Sci U S A. 1976 Apr;73(4):1260-4 PMID: 1063407
  46. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes.
    Cell. 1984 Oct;38(3):627-37 PMID: 6488314
  47. High expression of cloned immunoglobulin kappa gene in transgenic mice is restricted to B lymphocytes.
    Nature. 1984 Jul 19-25;310(5974):238-41 PMID: 6431295
  48. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes.
    Nature. 1985 May 9-15;315(6015):115-22 PMID: 2986015
  49. Isolation and expression of an altered mouse dihydrofolate reductase cDNA.
    Proc Natl Acad Sci U S A. 1983 May;80(9):2495-9 PMID: 6573667
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.6.6.2158-2167.1986
Published
1986-06-00
Pages
2158-67
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC367756
Subset
IM
Grants
NICHD NIH HHS · HD20484 · United States
External Links
PubMed source DOI: 10.1128/mcb.6.6.2158-2167.1986 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2